Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library
Identification and biological evaluation of a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical library
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DOI：
10.1158/0008-5472.can-07-0477
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发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Koumenis, Constantinos
中科院分区：
文献类型：
--
作者：
Lally, Brian E.;Geiger, Geoffrey A.;Koumenis, Constantinos
对于实体瘤患者，周围组织的耐受性通常限制了可以输送的辐射剂量。因此，优先增加放射对肿瘤细胞的细胞毒性作用的药剂将显著改变治疗比率并提高患者存活率。采用高通量、无偏筛选方法，我们在体外和体内鉴定了4 '-溴-3'-硝基苯丙酮（NS-123）作为人脑胶质瘤细胞的放射增敏剂。NS-123放射增敏U251胶质瘤细胞的剂量依赖性和时间依赖性的方式，剂量增强比范围从1.3到2.0。HT-29结直肠癌和A549肺腺癌细胞也在体外被NS-123放射增敏，而NS-123并不增加正常人星形胶质细胞的放射敏感性或照射斑马鱼胚胎的发育异常或致死率。在将U251细胞植入斑马鱼胚胎的新型异种移植模型中，NS-123增强了电离辐射（IR）的肿瘤生长抑制作用，对胚胎发育没有明显影响。使用小鼠肿瘤异种移植模型获得了类似的结果，其中NS-123使U251肿瘤对IR敏感，同时不显示明显的毒性。体外NS-123预处理导致IR诱导的未修复DNA链断裂的积累和IR后DNA损伤的替代标志物H2 AX、共济失调毛细血管扩张突变蛋白、DNA依赖性蛋白激酶和CHK 2的磷酸化延长，表明NS-123抑制DNA修复途径中的关键步骤。这些结果显示了这种基于细胞的高通量筛选方法鉴定新型放射增敏剂的潜力，并表明NS-123和类似的硝基苯酚化合物可能在抗神经胶质瘤模式中有效。
For patients with solid tumors, the tolerance of surrounding tissues often limits the dose of radiation that can be delivered. Thus, agents that preferentially increase the cytotoxic effects of radiation toward tumor cells would significantly alter the therapeutic ratio and improve patient survival. Using a high-throughput, unbiased screening approach, we have identified 4 '-bromo-3 '-nitropropiophenone (NS-123) as a radiosensitizer of human glioma cells in vitro and in vivo. NS-123 radiosensitized U251 glioma cells in a dose-dependent and time-dependent manner, with dose enhancement ratios ranging from 1.3 to 2.0. HT-29 colorectal carcinoma and A549 lung adenocarcinoma cells were also radiosensitized by NS-123 in vitro, whereas NS-123 did not increase the radiation sensitivity of normal human astrocytes or developmental abnormalities or lethality of irradiated Zebrafish embryos. In a novel xenograft model of U251 cells implanted into Zebrafish embryos, NS-123 enhanced the tumor growth-inhibitory effects of ionizing radiation (IR) with no apparent effect on embryo development. Similar results were obtained using a mouse tumor xenograft model in which NS-123 sensitized U251 tumors to IR while exhibiting no overt toxicity. In vitro pretreatment with NS-123 resulted in accumulation of unrepaired IR-induced DNA strand breaks and prolonged phosphorylation of the surrogate markers of DNA damage H2AX, ataxia telangiectasia mutated protein, DNA-dependent protein kinase, and CHK2 after IR, suggesting that NS-123 inhibits a critical step in the DNA repair pathway. These results show the potential of this cell-based, high-throughput screening method to identify novel radiosensitizers and suggest that NS-123 and similar nitrophenol compounds may be effective in antiglioma modalities.